Project Summary: Despite the acceptance of the glomerular podocyte as the target cell for injury in proteinuric kidney disease, cell-specific therapy remains absent in clinical nephrology. A critical barrier is the limited understanding of the mechanisms of podocyte injury during disease. Our preliminary data has identified KIBRA (KIdney BRAin protein) as a potential mediator of podocyte injury. KIBRA's expression is increased in human disease, and silencing of KIBRA in podocytes is protective in vitro and in vivo. We have demonstrated that KIBRA inhibits the signaling of the Hippo pathway effector Yes-associated protein (YAP) and disrupts normal actin cytoskeletal dynamics. KIBRA expression was also increased in Tgfbr1 transgenic mice and in CD2AP knockdown podocytes. Our central hypothesis is that TGF- ?/Smad signaling leads to upregulation of KIBRA in podocytes, resulting in podocyte injury. Additionally, as a disease correlate, we hypothesize that KIBRA overexpression will be sufficient to induce and promote glomerular disease progression, while KIBRA deletion in models of chronic glomerular disease will be protective. The rationale for the proposed research is that defining the role of KIBRA in glomerular disease progression will increase understanding of the mechanisms of podocyte injury and advance the quest for targeted therapeutics. Our hypothesis will be tested by three Specific Aims: Aim 1 will define the upstream regulation of increased KIBRA expression in podocytes. Aim 2 will determine whether KIBRA overexpression in podocytes promotes glomerular disease progression in vivo. Aim 3 will determine if KIBRA deletion reduces podocyte injury in chronic glomerular disease. Candidate and Training: The primary objective of this application is to support Dr. Kristin Meliambro's career development into an independent basic scientist in the fields of podocyte cell biology and glomerular diseases. Dr. Meliambro's proposed training activities are in four areas: 1) animal models of glomerular diseases, acute kidney injury (AKI), and chronic kidney disease (CKD); 2) podocyte cell biology and cell signaling, with a focus on the Hippo signaling pathway; 3) advanced imaging techniques; 4) scientific writing and oratory skills. To achieve this, she has assembled a mentoring and advisory team led by Dr. John Cijiang He, Chief of the Division of Nephrology, and Dr. Kirk Campbell, Associate Professor and Director of the Nephrology Fellowship Program at the Icahn School of Medicine at Mount Sinai (ISMMS). Both Drs. He and Campbell are former K08 awardees with combined four R01 grants between them who have expertise in the field of podocyte cell biology. Environment: The ISMMS is an international leader in medical and scientific training, biomedical research, and patient care. Research is a top priority, as ISMMS is ranked 13th among U.S. medical schools for NIH funding by US News and World Report and 2nd in research dollars per principal investigator by the Association of American Medical Colleges (AAMC). The Division of Nephrology at ISMMS is an international leader in research, particularly in the area of podocyte cell biology.